There has been much interest in recent years in the possible role
of endogenous opioid peptides (endorphins) in depression (1). The
high concentrates of opioid receptors and endorphins in limbic and
hypothalamic regions, and their interaction with noradrenergic and
dopaminergic systems, suggests involvement of endorphin systems in
depression, as do certain clinical observations. These include
anecdotal reports from the prepsychotropic era of the efficacy of
opiates in depression, the appearance in some detoxified opiate
addicts of depression responsive to opiates and antidepressants (2),
and reports of improvement in some depressed patients following
beta-endorphin (3). These observations, as well as the euphoric,
analgesic, and calming effect of opiates, suggest that decreased
functional activity in endorphin systems may be involved in the
pathophysiology of depression.

In order to test this endorphin hypothesis of depression and to
explore the possible efficacy of opiates in depression, the
investigators administered single doses of methadone and morphine to
depressed patients. Clinical and neuroendocrine responses were
measured.

All subjects gave written informed consent to participate. The
first experiment was an open investigation in 10 patients with major
depressive disorder by Research Diagnostic Criteria (4) (9 unipolar,
1 bipolar; 5 male, 5 female; mean age = 44 ± 5). The control group was comprised of two
normal volunteers and four inpatients with personality disorders (2
male, 4 female; mean age = 33 ± 8).
Patients with recent neuroleptic use were excluded, and patients
received no medication except flurazepam for at least 1 wk prior to
the study. After an overnight fast, subjects were at bedrest for
placement of an indwelling venous catheter through which 5 mg of
morphine were infused at 9:00 a.m. Samples of blood were obtained
via the catheter before, and 30, 60, 90, 120, and 180 min after,
morphine infusion for assay of serum prolactin (PRL) in duplicate by
radioimmunoassay (5). Each subject filled out an adjective checklist
self-rating scale before the infusion and at the time of each blood
drawing.

The second experiment was a double-blind, placebo-controlled
investigation in six inpatients with major depressive disorder by
Research Diagnostic Criteria (4) (2 unipolar, 4 bipolar; 2 male, 4
female; mean age =48 ± 4). None of the
patients received any active medication for at least 2 wk prior to
the study. Patients were at bedrest after an overnight fast for
placement of an indwelling venous catheter through which 5 mg of
methadone or saline placebo were infused at 9:30 a.m. Samples of
blood were obtained in four of the patients via the catheter 60, 30,
and 0 min before, and 15, 30, 60, 120, and 180 min after, the
infusion for assay of plasma PRL and cortisol by radioimmunoassay
and competitive protein binding, respectively. Clinical assessment
was performed by Brief Psychiatric Rating Scale (BPRS) and NIMH
self-rating scales before, and 15, 30, 60, 120, and 180 min after,
infusion.

FIGURE 1. Effects of 5 mg intravenous morphine on self-rated mood
in patients with major depressive disorder and controls.

FIGURE 2. Effects of 5 mg intravenous morphine of serum prolactin
in patients with major depressive disorder and controls.

In the first experiment, morphine infusion produced only small
nonsignificant antidepressant and antianxiety effects in both the
depressed and control groups (see Figure 1). Baseline PRL (mean in
ng/ml ± SEM) of 10.5 ± 1.9 for depressed patients and 9.0 ± 1.4 for controls did not differ. D PRL (peak minus baseline) of 7.2 ± 2.7 in the depressed patients was lower than
that of 31.9 ± 9.5 in controls (p<0.01
by two-tailed t-test; see Figure 2).

In the second experiment, all six patients correctly
distinguished the active methadone from the inactive saline
infusion. Three of the six reported themselves "better" two the
"same," and one "worse" 30 min after methadone infusion, whereas all
six patients reported themselves the "same" 30 min after saline
infusion. The methadone infusion produced little change according to
BPRS and self-rating scales (see (Figure ). Methadone, but not
placebo, produced large increases in plasma PRL (see Figure 4).
Serum cortisol 180 min after saline infusion was significantly lower
than cortisol 180 min after saline infusion (p<0.01; see Figure
5).

The well-documented increase in serum PRL produced in normals by
opiates and endorphins is thought to be mediated in part by
inhibitory opiate receptors on dopaminergic neurons (5-9). The
blunted PRL response to morphine in depressed patients may be
related to subtle changes in baseline PRL secretion or diurnal
pattern and may reflect changes in endorphin, dopamine, serotonin,
or other neuronal systems. This blunted response is consistent with
an opiate receptor deficit, or presence of excess of an endogenous
opioid antagonist, in major depressive disorder. The elevation of
PRL in depressed patients after 5 mg of methadone, which is about
twice as potent as morphine, suggests that depressed patients are
not refractory to the neurodendocrine effects of opiates but may
require a higher dose to achieve the same effect as in normals. The
decrease in plasma cortisol following methadone is interesting in
view of the known hypercortisol secretion in depression. Since ACTH
and beta- endorphin have a common precursor (1), methadone may exert
a feedback inhibition on ACTH and cortisol secretion.

FIGURE 4. Effects of 5 mg intravenous methadone and placebo on
plasma prolactin in patients with major depressive disorder.

FIGURE 5. Effects of 5 mg intravenous methadone and placebo on
plasma cortisol I patients with major depressive disorder.

Despite the lack of clear clinical antidepressant effects of
single doses of opioids, the neuroendocrine results reported here
suggest dysfunction in central endorphin systems in depression. The
results support the need for further investigation of these
neuroendocrine findings as well as possible antidepressant effects
of opioids, endorphins, and analogues in depression and other
psychiatric disorders (1-3,5,7,9,10).